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I. Introduction
Me0 ,
\ /
OMe
OMe
1 R-OMe 8 R=OMe
2 R = H 4 R = H
8 1-8
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 265
e2
a Hofmann degradation, and further chemical manipulation ( 5 ) .
N+
M e O OMe
e Me
M e
Me0
0
10 Me0 ' 11
13
266 R. H. F. MANSKE
10. Argemone mzlnita Dur. and Hilg. (XII, 335; XIII, 398; XIV, 512)
2,9-Dimethoxy-3-hydroxypavinane(13) (C,,H,,O,N; mp 197-198";
[a];'- 254") was isolated from this plant. Its structure was confirmed
by a total synthesis involving the penultimate 1,2-dihydroisoquinoline
and its cyclization with formic and phosphoric acids (10).
$
p--Q
0 -- OH Me OMe
\ \
OH 0
14
0 OH
OH 0
15
16 17
OH
18 19
19a
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 269
presence of sodium hydride. The product (mp 128') had UV, IR, NMR,
and mass spectra identical with those of bellendine (mp 162') (18a).
18. Camptothecine (XII, 464, XIV, 515)
The potent antileukemic and antitumor activity of this alkaloid
served to inspire other syntheses of it. The keto acid 20 (19) was
reduced with sodium borohydride to 21 and the latter on an a-methyl-
ene lactam rearrangement in acetic anhydride generated 22 as a
mixture of isomers. Oxidation of the latter with selenium dioxide in
acetic acid gave 23. Hydrolysis of 23 gave 24 and this on heating with
excess trimethyl orthobutyrate in the presence of a trace of propionic
acid gave a mixture which was hydrolyzed to 25. Oxidation of 25 to
the corresponding ketone (26) was achieved by means of dicyclo-
hexylcarbodiimide in DMSO. The latter, when condensed with N -
(2-aminobenzylidine)-p-toluidineunder the Friedliinder conditions
gave 27. The subsequent reactions to achieve the synthesis involved
aromatization of the pyridine ring and the formation of the a-hydroxyl-
actone. This was achieved by selenium dioxide oxidation in acetic
acid, and the resulting deoxycomptothecine (28) on further oxidation
(CuC1,-DMF-0,) was converted into camptothecine (29) (20).
In another synthesis of this alkaloid the tricyclic lactone 30 was
prepared by a series of reactions in which most of the steps gave
satisfactory yields. Hydrolysis with aqueous oxalic acid and con-
densation with anthraniladehyde generated compound 31 which had
already been converted into camptothecine (21). It should be added
that the early promise of this alkaloid as a therapeutic agent in cancer
therapy has not been confirmed in clinical trials (22).
Still another synthesis has been announced. Compound 33 was
obtained by heating 32 with diethyl acetonedicarboxylate and then
converted to 34 by heating with piperidine in acetonitrile. The latter
was hydrolyzed and decarboxylated by heating with concentrated
hydrochloric acid a t 150" to 35 which was methylated to 36 with
dimethyl sulfate and alkali, and this in turn converted to the aldehyde
37 by the Vilsmeier reaction. Reduction of 37 gave 38, formylation of
which gave 39 and then 40 by another Vilsmeier reaction and the latter
in turn was condensed with di-t-butyl malonate to 41, reduction of
which with sodium borohydride generated 42. Lactone formation and
deformylation of 42 by treatment with hydrochloric acid gave 43,
and this on dehydrogenation with dicyanodichloroquinone (DDQ)
afforded 44. Finally, ethylation of 44 with ethyl iodide and sodium
hydride gave 28 convertible into dl-camptothecine (29) by oxidation
(2323).
270 R. H. F. MANSKE
20 X + Y = O 22 23 X = H , Y = CH3.CO2, R = CH3.CO
21 X = H, Y = OH 24 X = H, Y = OH, R = H
25 X = H , Y =OH 27 28 R = H 0
26 X + Y = O 29 R = O H
0 0
30 31
AR- N
b
38 R = H
33 R = -CO.CHZ.CO.CH2.CO2Et
R'
34 R = -COzEt, R' = OH, R2 = H
35 R = R2 = H, R' = OH
36 R = R2 = H, R' = OMe
37 R. = H, R' = OMe, R2 = -CHO
6. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE 271
R H /
TT %
R'
38 R = RZ = H, R' = OMe
0 OMe
\'0
,c=o
c'
44
45 0
0
46
(:at-$
47 48
H'
OMe
49 50 51
(o \ O -3
q
H'
0 OMe 0
52 5a 54
R'
RQ
MeO"
55 R + R' = O.CHZ.0 57 R + R' = O.CHa.0
56 R = R 1= OMe 58 R = OMe, R' ::OH
I9 R = R ' = OMe
structures are as follows: alkaloid 11, [.ID + 76" (55); 111, [.ID + 118"
(56); IV, [a],,+123" (57); V, mp 150-152", [a],,+115" (58); VI,
[.ID +122" (59) (30).
81
CHa*CH:CH,
62
Me
63 Me0 /
64 R = H
65 R = M e
(F
66 67
Me Me Me
H I I
I
O y 7 (N]
Ro\
\ CH, C H 'H
0L O I
I
H I H
Ph Ph
68 69 70 R = H
71 R = P h * C O .
72
OAQ
71 R = O
74 R = H, OH
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 277
75 H 76
Me Me Me
OAC
77 78 R = COzH 80
79 R = -CH,.CO.Me
81 82 81 R = O
84 R = H,
Ho& 0 ".H
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 279
I
Me
89 OAc
90 x=(
‘H
91 x=o
o@ AcO Ac
---Me
0
N-
Me
96 X=O,R=OH
Me OAc
92 R = H, R1 = AC 96 X = ( ,R=OH
98 R = OH, R’ = AC ‘H
94 R = O H , R ’ = H 97 X = O , R = H
0
98 99
0
\
100 101 102
6. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE 283
0
OM0
108 R = Me 101
104 R = H
108
1078 108
284 R. 3.F. MANSKE
Me
113
R R' Ph
114 R =R' = P h 118
115 R = CsHll-, R' = CTHT5-
118 R = C,H:,-; R' = -CHz.CH(OH)(CHz),-Me
117 R = Ph, R' = -CHz.CH(OH)(CH2),.Me
aw3
120 x = 0 128 R = -CO.CHz.CHz.CH=CHP
124 R = -CO .CH,.CHZ.CHO
R ) T k O R 1
CH2 * Ph 0 0
124a R = H,R' = -CO.Ph 125 126
lZ4b R = H,R1 = -CO*Me
124~ R = Ph.CO,-, R' = H
124d R = OH, R' = -CO*CH=CH.Ph
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 287
shown that the structure originally proposed is in error. The amino
alcohol 122 on reaction with 4-pentenoyl chloride generated 123. The
latter was first oxidized to the corresponding ketone with chromic
oxide in pyridine and then to the aldehyde 124 with sodium periodate
and osmium tetroxide. Compound 124 was identical with isolongi-
strobine (96).
NH I
Me0
Me0
OH
130
93. Murraya koenigii Spreng. (Rutaceae) (XII, 491; XIII, 274, 414)
Murrazoline isolated from the stem bark has structure 133 as deter-
mined by spectral studies which chemical reactions confirmed (118).
OMe Me0
Me
OH
133 1a4
Me
HO GQ Me
iaa 136
6. ALKALOIDS UNCLASSITIED AND OF UNKNOWN STRUCTURE 291
&
Orixinone (Cl7Hl9O5N; mp 10ZO),a new alkaloid, was shown to
have structure 140, largely by means of spectral data and confirmed by
~~p~
dehydration of orixine (141). The quaternary 0-methylbalfouradinium
ion was also isolated as its perchlorate (129).
MHe 0 O T
Me0
Ph * CH2-T \
0
Me0 ' N
I
0
CHa. Ph Me
137 138 139
OMe OCH@Me
\
Q-0 L O N
140 141 142
R 0
I
143 R = OH 145
144 R -CHI. CO .M e
E
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 293
146 147
(o \ O P - 148
2 94 R. H. F. MANSKE
108. Piper sylvaticum Roxb. (Piperaceae) (XII, 495; XIII, 417; XIV,
557)
Sylvatine (C,,H3,03N; mp 112'; [a]D k 0') isolated from this plant
was shown to be an amide of piperic acid. Mass and other spectra
indicated structure 148 and confirmation was achieved by reduction,
hydrolysis, and/or oxidation, the product of the latter process being
5-methylhexanoic acid (136).
109. Pisum sativum L. (Leguminosae) (XIV, 551)
Cadaverine was present in concentration of 2 5 pg/g of fresh young
plants grown under various conditions (137).
Me
149 R = Me, R' = H 151 152
150 R = H, R' = Me
SYL 161
COaH
mNH2
OAc
165
OAo
164
129. Spathelia sorbifolia (L) Fawc. & Rendle (Rutaceae) (XII, 480)
N-Methylflindersine (mp 83-85'), not previously recognized as a
natural product, was isolated by a procedure involving chromatography.
Spectral examination indicated its identity although no chemical
transformations were reported. This plant had at one time been placed
in Simarubaceae but the chemical constituents along with some
taxonomic studies indicate the above relegation (162).
revised structure 167 has been suggested. Two minor alkaloids, also
isolated, were shown to be d-septicine and d-isotylocrebrine (166).
0
OMe
OM.3
165 166 167
v OMe
168
M e O - e C H . CHz. N H R
169
_ . I
OH
R = Ph.CO.
170 R = Ph.CH=CH.CO.
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6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 303